Perindopril PLUS Indapamide, 1.25mg+4 mg 30 pcs

Pharmgroup:

Antihypertensive drug.

Pharmacological action:

Combined product containing perindopril (ACE inhibitor) and indapamide (diuretic of sulfonamide group). The pharmacological effect of the drug is due to the combination of the individual properties of each of the components, the combination of which enhances the effect of each other. The drug has antihypertensive, diuretic, vasodilator and cardioprotective effects.

Perindopril PLUS Indapamide has dose-dependent significant hypotensive effect on systolic and diastolic BP in prone position and while standing irrespective of the patient’s age and body position. The action of the drug lasts for 24 hours. Stable clinical effect occurs in less than 1 month from the beginning of therapy and is not accompanied by tachycardia. Discontinuation of therapy is not accompanied by development of withdrawal syndrome.

Perindopril PLUS Indapamide decreases the degree of left ventricular hypertrophy, improves arterial elasticity, decreases PPS, has no effect on lipid metabolism (total cholesterol, HDL, LDL, triglyceride) and does not affect carbohydrate metabolism (including in diabetic patients).

Perindopril belongs to the group of ACE inhibitors and has hypotensive, vasodilator, cardioprotective, natriuretic effects. It inactivates ACE in plasma, endothelium of the vascular wall, possibly in the cells of renal glomeruli and tubules, lung, heart, adrenal and brain tissue. Reduces angiotensin II levels in blood and tissues, decreases production and release of aldosterone from adrenal glands, inhibits release of noradrenaline from sympathetic nerve fiber endings and endothelin formation in vascular wall, increases concentration of bradykinin, vasodilator prostaglandins. Increases the activity of kallikrein-kinin system, stabilizes the level of atrial natriuretic peptide.

The decrease of angiotensin II formation is accompanied by an increase of blood plasma renin activity.
Reduces PPS, BP (without development of tachycardia), left ventricular filling pressure. Arterial and venous vasodilation is accompanied by weakening of post- and preload on the myocardium, reduction of end diastolic pressure in the ventricles of the heart, a moderate decrease in heart rate, increase in cardiac output. It improves regional (coronary, cerebral, renal, muscular) blood flow, reduces myocardial oxygen demand in CHD.

Inhibiting tissue renin-angiotensin systems, it has cardioprotective effect (reduces left ventricular hypertrophy) and angioprotective effect (prevents hyperplasia and proliferation of vascular smooth muscle cells, induces reverse development of vascular wall hypertrophy, restores elasticity of large vessels and endothelial function, including the ability to release oxytocin.including the ability to release nitric oxide, endothelial relaxing factor).

Inhibits the development of tolerance to nitrates and increases their vasodilating effect.
In patients with chronic heart failure it statistically reliably decreases the severity of clinical symptoms and increases exercise tolerance. It does not cause BP fluctuations after the first dose and during long-term therapy.

Indapamide by its pharmacological properties is close to thiazide diuretics (it disrupts sodium ions reabsorption in cortical segment of the Genle loop); it has hypotensive, diuretic and vasodilator effects. It increases urinary excretion of sodium and chlorine ions and, to a lesser extent, potassium and magnesium ions. It has the ability to selectively block slow calcium channels, increases elasticity of arterial walls and decreases ARPS. Helps reduce left ventricular hypertrophy. It reduces the sensitivity of the vascular wall to noradrenaline and angiotensin II, stimulates the synthesis of prostaglandin PgE2 and prostacyclin PgI2, reduces the production of free and stable oxygen radicals.

The hypotensive effect of indapamide is manifested in doses with little or no diuretic effect.

Pharmacokinetics:

The pharmacokinetic parameters of perindopril and indapamide are unchanged when combined compared to their separate use.

1. Perindopril
When administered orally, perindopril is rapidly absorbed from the GI tract. Bioavailability is 65-95%, decreasing by 35% with concomitant food intake. Cmax is reached after 1 hour and decreases to 33-44% by the end of the day.
During metabolism perindopril is biotransformed to form the active metabolite perindoprilat (about 20%) and five inactive compounds. Cmax of perindoprilat is reached after 3-4 hours.

The binding to plasma proteins is insignificant, less than 30% and depends on the drug concentration. Vd of free perindoprilat is 0.2 l/kg.

Repeated administration of perindopril does not result in its cumulation and the T1/2 of perindoprilat when repeatedly administered corresponds to its period of activity. Css on repeat administration is reached in 4 days.

Perindoprilat is excreted by the kidneys. The T1/2 of the free fraction of the metabolite is 3-5 h. Slowly dissociates from binding to ACE, therefore the T1/2 corresponding to the activity of the drug is 25-30 hours.

Pharmacokinetics in special clinical cases:

In elderly patients as well as in patients with renal and cardiac insufficiency, excretion of perindopril is delayed (dosing regimen correction is necessary). Dialysis clearance of perindopril is 70 ml/min.
In patients with cirrhosis hepatic clearance of perindopril is decreased by half, while the total amount of perindoprilate produced does not change and dosing regimen adjustment is not required.

2. indapamide

Indapamide is rapidly and completely absorbed from the gastrointestinal tract after oral administration; bioavailability is high. Food intake slows down a little the speed of absorption, but does not affect the total amount of absorbed drug. TCmax in blood plasma is 1-2 hours after oral administration. Fluctuations in plasma concentrations between 2 doses are reduced with repeated administration. Css is established after 7 days of regular administration.

The binding to plasma proteins is 71-79%. Indapamide also binds to the elastin of the smooth muscles of the vascular wall. It has a high Vd. Permits through histohematic barriers (including placental). It does not cumulate.

It is metabolized in the liver. T1/2 is 14-24 hours (on the average 19 hours). The kidneys excrete 60-70% as metabolites (about 5-7% unchanged), the intestines excrete 20-23%.

Pharmacokinetics in special clinical cases:
In patients with renal insufficiency pharmacokinetics of indapamide does not change.

Indications

– Arterial hypertension.

Active ingredient

How to take, the dosage

Perindopril PLUS Indapamide is taken orally once daily at the same time (preferably in the morning), before meals.
Adults, including elderly patients, are prescribed 1 tablet. 1 time per day.

The maintenance dose is chosen individually depending on the tolerability of the preparation, therapeutic effect and condition of the patient.
The tablets are taken whole without chewing.

Interaction

Perindopril PLUS Indapamide increases the severity of hypoglycemic action of insulin and sulfonylurea drugs (by increasing glucose tolerance and reducing the need for insulin).

Baclofen, tricyclic antidepressants, antipsychotic drugs (neuroleptics), beta-adrenoblockers (including with significant systemic absorption from ophthalmic dosage forms), saluretics, alcohol, other antihypertensive agents increase the hypotensive effect and increase the risk of orthostatic hypotension (additive effect). It is necessary to monitor the BP and adjust the dose of the drug.

When Perindopril Plus is used together with muscle relaxants or drugs used for anesthesia the hypotensive effect may increase. The risk of severe arterial hypotension can be reduced by stopping diuretics several days before treatment with Perindopril Plus.

Co-administration with sympathomimetics, GCS, NSAIDs, estrogens may decrease the hypotensive effect of Perindopril Plus.

Cyclosporine, potassium-saving diuretics, potassium preparations increase the risk of hyperkalemia. Concomitant use of drugs that may cause hyperkalemia and ACE inhibitors is not recommended except in cases of severe hypokalemia.
Concomitant use of Perindopril Plus with myelodepressants, interferon increases the risk of neutropenia and/or agranulocytosis with fatal outcome.

When used concomitantly with lithium preparations perindopril increases the concentration of lithium and its toxic effects.
Antacids and tetracyclines reduce the rate and completeness of absorption of the drug from the gastrointestinal tract.
Cyclosporine increases the risk of renal dysfunction (hypercreatininemia).
Simultaneous use of erythromycin (intravenous), pentamidine, sulfopride, vincamine, halofantrine, bepridil and indapamide as well as antiarrhythmic agents of I A and III classes may cause “pirouette” arrhythmia.

In concomitant use of Perindopril Plus and NSAIDs in case of dehydration of the body it is possible to develop acute renal failure (due to decreased glomerular filtration). In such cases it is necessary to ensure sufficient body hydration and evaluate renal functional activity before the treatment start.

Prior to the use of iodine-containing contrast agents, rehydration should be performed to reduce the risk of renal failure with diuretics.

Concomitant use with calcium salts may increase plasma calcium content as a result of decreased excretion in the urine.

Special Instructions

Perindopril PLUS Indapamide:
Treatment should be supervised by a physician.

Perindopril PLUS Indapamide may cause a sharp decrease in BP, especially when first taking the drug and during the first 2 weeks of therapy. Risk of excessive BP decrease is increased in patients with decreased BOD (as a result of strict non-salt diet, hemodialysis, vomiting and diarrhea), with severe heart failure (both with and without associated renal failure), with initially low BP, with bilateral renal artery stenosis or stenosis of the artery of a single kidney, cirrhosis of the liver, accompanied with edema and ascites. Significant BP decrease during the first drug administration is not an obstacle for its further prescription. After restoration of the RBC and BP, treatment may be continued with a lower dose of the drug or with monotherapy with one of its components.

The electrolyte concentrations (potassium, sodium, magnesium), glucose, uric acid, plasma creatinine and pH should be systematically monitored during treatment. In elderly patients, weakened patients taking several different drugs, patients with cirrhosis, patients with edema or ascites, patients with CHD or heart failure, the risk of potassium concentration decrease below the permissible level (less than 3.4 mmol/l) should be considered. Decreased potassium levels increase the toxicity of cardiac glycosides and increase the risk of arrhythmias.

Perindopril PLUS Indapamide has lactose as an excipient. As a consequence, this drug is not recommended for persons with lactase deficiency, galactosemia, or glucose-galactose malabsorption syndrome.

The drug should be discontinued before the upcoming surgical treatment (12 hours).

During treatment it is recommended to avoid alcohol consumption.
1. Perindopril:
It is recommended to determine creatinine, electrolyte and urea concentrations (for 1 month) before and during therapy. In patients who received diuretics, they should be discontinued 3 days before treatment with perindopril, and against the background of chronic heart failure, the doses should be reduced (to reduce the risk of orthostatic hypotension). During therapy it is necessary to monitor blood pressure, to provide continuous peripheral blood monitoring (before treatment, during the first 3-6 months of treatment and further at intervals during 1 year, especially in patients with increased risk of neutropenia), protein, plasma potassium, urea nitrogen, creatinine, renal function, body weight, diet.

In patients at risk, especially those with decompensated chronic heart failure, elderly patients, and patients with baseline low BP, impaired renal function, or those receiving high doses of diuretics, initiation of the drug should be under medical supervision.

People with renal artery stenosis or with hyponatremia may experience a rapid onset of hypotension and acute renal failure.

Hyperkalemia may develop during treatment with perindopril, especially in the presence of renal and/or heart failure.

In patients on hemodialysis, the use of polyacrylonitrile membranes should be avoided (possible development of anaphylactoid reactions).

Caution should be used with renovascular hypertension, severe autoimmune diseases, aortic or mitral stenosis, constrictive pericarditis, hypertrophic cardiomyopathy with hemodynamic disorders, presence of obstructive changes impeding blood outflow from the heart bilateral renal artery stenosis or renal artery stenosis of a single kidney, presence of a transplanted kidney, obliterating atherosclerosis of lower limb arteries, widespread atherosclerosis with lesions of coronary and carotid arteries, in moderate renal failure, hyperkalemia (5 to 5.5 mmol/l), hyponatremia or sodium restriction in the diet, dehydration, leukopenia, thrombocytopenia.

Caution is required if any surgical interventions (including dental) are performed during treatment.
2. Indapamide:
In patients taking cardiac glycosides, laxatives, with hyperaldosteronism, as well as in the elderly, careful monitoring of potassium and creatinine is indicated.

The most careful control is indicated in patients with cirrhosis (especially with edema or ascites – the risk of metabolic alkalosis, increasing the manifestations of hepatic encephalopathy), CHD, chronic heart failure. Patients with prolonged QT interval on ECG are also at high risk. The first determination of blood potassium concentration should be performed within 1 week of treatment.

Hypercalcemia on Indapamide administration may be due to previously undiagnosed hyperparathyroidism.
In patients with diabetes it is extremely important to monitor blood glucose, especially in the presence of hypokalemia.
Significant dehydration may lead to acute renal failure (decreased glomerular filtration).
Patients need to compensate for water loss and carefully monitor renal function at the beginning of treatment.
Indapamide may give positive results in doping control.

The effect on the ability to drive and operate machinery:

Due to the risk of arterial hypotension and dizziness when taking the drug (especially at the beginning of therapy), patients should exercise caution when driving vehicles and performing work requiring increased concentration and rapid psychomotor reactions.

Contraindications

– history of angioneurotic edema;
– hypokalemia;
– severe renal insufficiency (CK < 30 ml/min);
– expressed hepatic insufficiency (including. Severe hepatic insufficiency (including encephalopathy);
– concurrent use of QT interval prolonging agents;
– II and III trimesters of pregnancy;
– Breast-feeding;
– Child and adolescent age less than 18 years;
– Hypersensitivity to the components of Perindopril PLUS Indapamide;
– Hypersensitivity to other ACE inhibitors;
– Hypersensitivity to sulfonamides.

Side effects

In the recommended doses the drug is usually well tolerated.
Definition of the frequency of side effects: frequently (1-10%), rarely (0.1-1%), very rarely (less than 0.1%).
Perindopril Plus effects
Water and electrolyte balance: hypokalemia is possible. Perindopril as a component of the drug, which has the ability to increase the concentration of potassium by inhibiting the RAAS, leads to a decrease in potassium loss caused by indapamide.
1. Effects caused by perindopril:
Cardiovascular system: often – excessive decrease of BP and related symptoms, very rarely – arrhythmia, angina pectoris, myocardial infarction, stroke.
Urinary system: rarely – reduced renal function, very rare – acute renal failure. Slight increase of creatinine in urine and serum may occur (reversible after drug withdrawal) – most probably due to renal artery stenosis, treatment of arterial hypertension with diuretics, renal failure, temporary hyperkalemia, proteinuria (in patients with glomerular nephropathy).
The respiratory system: frequently – dry cough, difficulty in breathing, rarely – bronchospasm, very rare – rhinorrhea.
The digestive system: frequently – nausea, vomiting, abdominal pain, diarrhea, constipation, taste disorders, rarely – dry mouth, very rare – cholestatic jaundice, pancreatitis.
CNS and peripheral nervous system: often – headache, asthenia, dizziness, tinnitus, visual disturbances, muscle cramps, paraesthesias, taste disorders; rarely – mood and sleep disorders, very rare – confusion.
Blood system: rare – thrombocytopenia, decrease of hemoglobin and hematocrit; very rare – agranulocytosis, pancytopenia; against glucose-6-phosphate dehydrogenase deficiency hemolytic anemia may develop. Against the background of ACE inhibitors use in patients after kidney transplantation and hemodialysis patients anemia may develop.
Allergic reactions: common – skin rash, itching, rare – urticaria, angioedema, very rare – erythema multiforme.
Other: rare – increase in sweating, impaired sexual function.
2. Effects caused by the action of indapamide:
CNS and peripheral nervous system: rare – dizziness, headache, asthenia, paresthesias (usually disappear when reducing the drug dose).
The digestive system: rare – nausea, constipation, dry mouth, in some cases – pancreatitis, in liver failure – hepatic encephalopathy.
The electrolyte-water balance: hypokalemia is possible (especially in patients classified as risk group), sodium level decrease, accompanied by dehydration and orthostatic hypotension. Simultaneous loss of chlorine ions can lead to compensatory metabolic alkalosis (its frequency of occurrence and severity are low). In some cases the calcium level may increase.
Metabolism: increases in plasma urea and glucose may occur.
Blood system: in some cases – thrombocytopenia, leukopenia, agranulocytosis, aplastic anemia, hemolytic anemia.
Dermatological reactions: skin rashes, hemorrhagic vasculitis, exacerbation of SLE is possible.
Allergic reactions: in predisposed patients – skin manifestations.

Overdose

Symptoms: marked BP decrease, nausea, vomiting, convulsions, dizziness, insomnia, decreased mood, polyuria or oliguria that may turn into anuria (as a result of hypovolemia), disorders of water-electrolyte balance, bradycardia.

Treatment: dose reduction or complete abolition of the drug; gastric lavage, measures aimed at the increase of the circulatory volume (administration of saline and other blood replenishing fluids). If severe arterial hypotension develops, the patient should be given a horizontal position with his legs elevated. Symptomatic therapy – epinephrine (p/u or IV), antihistamines, hydrocortisone (IV), dialysis procedures (do not use highly permeable polyacrylonitrile membranes).
If bradycardia develops, atropine is used, an artificial pacemaker may be required.

Similarities